Melanoma development and pigment cell transformation in xiphophorus

Wellbrock, Claudia; Gómez, Ana; Schartl, Manfred

doi:10.1002/jemt.10163

Cited by 29 publications

(21 citation statements)

References 44 publications

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“…Normal human melanocytes express EGFR, ERBB2, ERBB3 and ERBB4, and stimulation with ligand promotes migration in vitro (Gordon-Thomson et al, 2001;Stove et al, 2003;Gordon-Thomson et al, 2005;Mirmohammadsadegh et al, 2005). ErbB receptors also are expressed in melanoma cells, and are associated with melanoma progression in a teleost model (Wellbrock et al, 2002;Gomez et al, 2004) and with human melanoma proliferation in vitro (Stove et al, 2003;Gordon-Thomson et al, 2005;Funes et al, 2006). Our finding that the picasso mutant phenotype results from lesions in erbb3b provides the first evidence that ErbB signals are required to promote normal pigment cell and pigment pattern development in vivo [although Fitch et al (Fitch et al, 2003) describe melanocytosis resulting from EGFR overexpression in skin].…”

Section: Discussionmentioning

confidence: 99%

Embryonic requirements for ErbB signaling in neural crest development and adult pigment pattern formation

2008

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Vertebrate pigment cells are derived from neural crest cells and are a useful system for studying neural crest-derived traits during post-embryonic development. In zebrafish, neural crest-derived melanophores differentiate during embryogenesis to produce stripes in the early larva. Dramatic changes to the pigment pattern occur subsequently during the larva-to-adult transformation, or metamorphosis. At this time, embryonic melanophores are replaced by newly differentiating metamorphic melanophores that form the adult stripes. Mutants with normal embryonic/early larval pigment patterns but defective adult patterns identify factors required uniquely to establish, maintain or recruit the latent precursors to metamorphic melanophores. We show that one such mutant, picasso, lacks most metamorphic melanophores and results from mutations in the ErbB gene erbb3b, which encodes an EGFR-like receptor tyrosine kinase. To identify critical periods for ErbB activities, we treated fish with pharmacological ErbB inhibitors and also knocked down erbb3b by morpholino injection. These analyses reveal an embryonic critical period for ErbB signaling in promoting later pigment pattern metamorphosis, despite the normal patterning of embryonic/early larval melanophores. We further demonstrate a peak requirement during neural crest migration that correlates with early defects in neural crest pathfinding and peripheral ganglion formation. Finally, we show that erbb3b activities are both autonomous and nonautonomous to the metamorphic melanophore lineage. These data identify a very early, embryonic, requirement for erbb3b in the development of much later metamorphic melanophores, and suggest complex modes by which ErbB signals promote adult pigment pattern development.

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Section: Discussionmentioning

confidence: 99%

Embryonic requirements for ErbB signaling in neural crest development and adult pigment pattern formation

2008

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“…Indeed, studies into cell signaling in a fish model for melanoma (10,11) and the use of earlystage MEK inhibitors such as PD908059 and U0126 (12,13) demonstrated the early activation of the MAPK-pathway during melanoma development in vivo, as well as its relevance for melanoma cell proliferation and its potential as therapeutic target. In 2002, Cohen et al reported constitutive ERK-phosphorylation in >20% of benign nevi and >80% of primary melanoma (14), and hence confirmed activation of MAPK-signaling as an early event in human melanoma development.…”

Section: Introductionmentioning

confidence: 99%

Overcoming resistance to BRAF inhibitors

2017

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Abstract:The discovery of activating mutations in the serine/threonine (S/T) kinase BRAF followed by a wave of follow-up research manifested that the MAPK-pathway plays a critical role in melanoma initiation and progression. BRAF and MEK inhibitors produce an unparalleled response rate in melanoma, but it is now clear that most responses are transient, and while some patients show long lasting responses the majority progress within 1 year. In accordance with the key role played by the MAPK-pathway in BRAF mutant melanomas, disease progression is mostly due to the appearance of drug-resistance mechanisms leading to restoration of MAPK-pathway activity. In the present article we will review the development, application and clinical effects of BRAF and MEK inhibitors both, as single agent and in combination in the context of targeted therapy in melanoma. We will then describe the most prominent mechanisms of resistance found in patients progressed on these targeted therapies. Finally we will discuss strategies for further optimizing the use of MAPK inhibitors and will describe the potential of alternative combination therapies to either delay the onset of resistance to MAPK inhibitors or directly target specific mechanisms of resistance to BRAF/ MEK inhibitors.

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“…Xmrk-driven melanoma formation in Xiphophorus is a model for receptor tyrosine kinase (RTK)-induced tumorigenesis and a well-established model for the molecular analysis of the successive steps in melanoma development (25,26). Overexpression and mutation of this variant of epidermal growth factor (EGF) receptor (EGFR) induces all molecular events to trigger melanoma formation in this model system (27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

The Oncogenic Epidermal Growth Factor Receptor Variant Xiphophorus Melanoma Receptor Kinase Induces Motility in Melanocytes by Modulation of Focal Adhesions

et al. 2006

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One of the most prominent features of malignant melanoma is the fast generation of metastasizing cells, resulting in the poor prognosis of patients with this tumor type. For this process, cells must gain the ability to migrate. The oncogenic receptor Xmrk (Xiphophorus melanoma receptor kinase) from the Xiphophorus melanoma system is a mutationally activated version of the epidermal growth factor receptor that induces the malignant transformation of pigment cells. Here, we show that the activation of Xmrk leads to a clear increase of pigment cell motility in a fyn-dependent manner. Stimulation of Xmrk induces its interaction with the focal adhesion kinase (FAK) and the interaction of active, receptor-bound fyn with FAK. This results in changes in FAK activity and induces the modulation of stress fibers and focal adhesions. Overexpression of dominant-negative FAK shows that the activity of innate FAK and a receptor-induced focal adhesion turnover are a prerequisite for pigment cell migration. Our findings show that in our system, Xmrk is sufficient for the induction of pigment cell motility and underlines a role of the src family protein tyrosine kinase fyn in melanoma development and progression. (Cancer Res 2006; 66(6): 3145-52)

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Melanoma development and pigment cell transformation in xiphophorus

Cited by 29 publications

References 44 publications

Embryonic requirements for ErbB signaling in neural crest development and adult pigment pattern formation

Embryonic requirements for ErbB signaling in neural crest development and adult pigment pattern formation

Overcoming resistance to BRAF inhibitors

The Oncogenic Epidermal Growth Factor Receptor Variant Xiphophorus Melanoma Receptor Kinase Induces Motility in Melanocytes by Modulation of Focal Adhesions

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